Targeting Novel Neurotrophin Effectors for Treating Post-Traumatic Epilepsy
Abstract
Traumatic brain injury (TBI) affects about 800,000 children each year and has been linked to various life-long disorders including epilepsy, depression, and intellectual impairment. Despite the prevalence of pediatric TBI, most TBI studies focus on adult animal models. Yet the developing brain exhibits a completely distinctive injury response so it can be difficult to extrapolate the results from adult models to pediatric TBI. Thus, there is an urgent need for research into the effects of pediatric TBI and potential remediation. Neurotrophins are secreted proteins that are important for early brain development and are known to be neuroprotective after injury. However their short biological half-life and poor blood-brain barrier permeability have made it difficult to use neurotrophins in clinical settings. One promising strategy is to target cellular effector proteins of neurotrophins that can be manipulated pharmacologically. Recently, we identified two novel effector proteins within the neurotrophic pathways named Par1 and HuD. These two proteins remain unexplored in TBI research. We found that the levels of these two proteins decrease significantly after pediatric TBI. We also found that both Par1 and HuD are important for brain development and disruption of either protein leads to poor cognitive functions and increased seizure susceptibility, which are symptoms often observed after pediatric TBI. Thus, in this proposal, we will test the molecular and cellular mechanisms by which Par1 and HuD are involved in the pediatric brain injury response, using multifaceted approaches including laser capture and quantitative real time PCR, 3D serial reconstruction, live two-photon in vivo imaging, biochemical and behavioral analyses. We will also use genetic and pharmacological approaches to stimulate the Par1-HuD pathway to determine whether we can promote regeneration and improve behavioral outcomes after pediatric TBI.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2020
- Accession Number
- AD1126096
Entities
People
- Huaye Zhang
Organizations
- Rutgers University